PROJECT SUMMARY Rationale: Cardiovascular (CV) disease is the leading cause of death for women and men in the US, accounting for one in every four deaths. In 2014, CV deaths among African-Americans were 30% higher than among non-Hispanic whites, and while CV mortality rates decreased for both blacks and whites over the past four decades, racial/ethnic disparities increased substantially. Despite considerable progress on the identification of behavioral, environmental, social, and economic mechanisms underlying racial/ethnic disparities in CV outcomes, little is known about the molecular mechanisms by which these socially-patterned risk factors become physically embodied. Although it has been proposed that epigenetic factors, such as DNA methylation (DNAm), may contribute to racial/ethnic disparities in CV outcomes, this hypothesis has yet to be empirically tested. Methods: The proposed study will examine DNAm patterns among African-American and non-Hispanic white participants in the US National Health and Nutrition Examination Survey (NHANES 1999-2002), a nationally representative population-based sample with detailed measures on potential underlying mechanisms of racial/ethnic differences in DNAm, including health behaviors, environmental toxicant exposures, and individual- and neighborhood-level social and economic factors, as well as genetic data to account for population stratification. We will perform genome-wide DNAm assays on >850,000 CpG sites using biobanked DNA from 535 African-American and 1,952 white individuals aged 50+ from NHANES 1999-2002. DNAm data will be linked to existing survey data, laboratory data, and 15-year mortality follow-up data to accomplish the following aims: (1) To quantify racial/ethnic differences in DNAm patterns, overall and by age, (2) To determine whether these differences are explained by factors already known to contribute to health disparities, such as sedentary behavior, lead exposure, food insecurity, poverty, and residential segregation, and (3) To determine whether racial/ethnic disparities in CV mortality are explained by differences in DNAm patterns. Relevance: By adding DNAm data from a diverse, nationally representative sample to the growing number of studies with methylomic data, the proposed study will help ensure the equitable translation of epigenomic discoveries into health applications, such as precision medicine initiatives, that will benefit the health of everyone in the US, including racial/ethnic minorities, the poor, and those who live outside large urban centers, all of whom tend to be underrepresented in genetic research. Moreover, DNAm data from this study will be made available to the public through the CDC Research Data Center, enabling others in the research community to explore additional critical hypotheses about the role of DNAm in producing racial/ethnic, socioeconomic, and rural disparities in a variety of health-related outcomes.